The therapeutic activities of some bile acids like, for instance, ursodeoxycholic, chenodeoxycholic, cholic and deoxycholic acids are well known for some time. Initially their use has been addressed to the dissolution of the cholesterol gall-stones, by virtue of their ability the cholesterol synthesis, helping the cholesterol removal through the formation of mixed micelles and to inhibit the cholesterol absorption in the intestine. Subsequently the bile acids were used to treat biliary dyspepsias, biliary cirrhosis and chronic and cholestatic hepatopathies, as described in Digestive Diseases, 8, (1), 12-22, (1990) by Leuschner U. and Kurz W.
The oral therapy with bile acids is till now carried out by means of the administration of the acids in the form of immediate or delayed release tablets or capsules. All these formulations have the drawback of giving an incomplete absorption, due to a scarce bioavailability as clearly shown by Parquet M. et al., European Journal of Clinical Investigation, 15, (4), 171-8, (1985), Igimi H., Corey M. C., J. Lip. Res., 21, 72-90, (1980) and Roda A., Fini A., Hepatology, 4, 72-6, (1984).
This scarce bioavailability is due to the fact that bile acids, particularly ursodeoxycholic acid, dissolve very slowly in the intestine after having crossed unabsorbed and undissolved the stomach.
The water solubility of free bile acids, mainly that of ursodeoxycholic acid, is very low (53 .mu.M) and, because of its restrained detergence (CMC=14 mM), its solubility little increases with the increase of the pH and the complete solubilization takes place only at pH 8.47.
Therefore, ursodeoxycholic acid is completely solubilized and absorbed only when the intestinal pH exceeds the value of 8.4, while at lower values of pH a portion of ursodeoxycholic acid is not absorbed and undergoes a biotransformation to litocholic acid by means of the intestinal bacterial flora.
Therefore it is easily understandable why delayed release formulations containing ursodeoxycholic acid actually can have a lesser bioavailability than that of immediate release formulations in case the delayed release takes place in the intestinal zones where a greater metabolization contemporaneously occurs together with a greater solubilization.
Overcoming the problems of scarce absorption of the immediate or delayed release formulations containing bile acids used at present, is the object of the present invention. This object is achieved by means of enterosoluble gastroresistant pharmaceutical formulations containing a mixture of bile acids and their salts with alkali metals or organic bases.
The pharmaceutical formulations must be gastroresistant, because otherwise the strongly acid gastric juices would release the bile acids from their salts so that there would be again the problem of the slow and incomplete intestinal solubilization of the acids themselves.
The pharmaceutical formulations object of the present invention represent a significant improvement in comparison with prior art because they assure a remarkable increase in active principle absorption and at the same time they allow a modulation of active principle release.
This modulation depends on both salified fraction of active principle, which is immediately solubilized and absorbed, and non-salified fraction, which is solubilized and absorbed more slowly, and it concerns with both the maximum plasma concentration (C max) of active principle and the time in which the maximum concentration is obtained (T max). The therapeutic goals consisting of an increase of the maximum plasmatic concentration (C max) and a quicker achievement of said concentration (T max) together with a better total bioavailability, are achieved by the pharmaceutical formulations object of the present invention as it is clearly shown by biological tests of bioavailability carried out on men, by using a pharmaceutical formulation prepared according to the present invention in comparison with a commercial pharmaceutical formulation of ursodeoxycholic acid.
The experimental results showed a remarkable increase of the bioavailability of the formulation prepared according to the present invention in comparison with the commercial formulation. The average increase of the bioavailability (AUC) is equal to about 30%. Moreover the maximum hematic concentration (C max) reaches average values that are more than twice higher and a quicker achievement of the maximum hematic peak (T max) is also noticed; in fact the formulation according to the present invention reached this peak in about 3 and half hours on the average while the commercial formulation reached it in about 4 hours and half.
These experimental data on men clearly show the full achievement of the objects of the invention and therefore the pharmaceutical formulations object of the present invention are perfectly suitable for the therapeutic uses of bile acids, mainly for the treatment of biliary calculoses, biliary dyspepsias, biliary cirrhosis and chronic and cholestatic hepatopathies.